JPH1147570A - Separation membrane and its preparation - Google Patents
Separation membrane and its preparationInfo
- Publication number
- JPH1147570A JPH1147570A JP9210518A JP21051897A JPH1147570A JP H1147570 A JPH1147570 A JP H1147570A JP 9210518 A JP9210518 A JP 9210518A JP 21051897 A JP21051897 A JP 21051897A JP H1147570 A JPH1147570 A JP H1147570A
- Authority
- JP
- Japan
- Prior art keywords
- separation membrane
- blood
- membrane
- polyalkylene glycol
- module
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Separation Using Semi-Permeable Membranes (AREA)
- External Artificial Organs (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、高い物質透過性能
と 抗血小板付着性を両立する分離膜及びそれを含む血
液浄化器に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a separation membrane having both high substance permeation performance and antiplatelet adhesion and a blood purifier including the same.
【０００２】[0002]
【従来の技術】現在、様々な高分子材料が医療分野で使
用されているが、人工血管、カテーテル、血液バッグ、
人工腎臓等の直接血液に接触する用具においては、血漿
蛋白や血小板等の血液成分の付着、及びこれに起因する
血栓の形成は避け難い問題である。特に血液浄化器に使
用される膜では、血液成分の付着が直接膜の性能低下に
つながるため重要な問題である。2. Description of the Related Art At present, various polymer materials are used in the medical field, but artificial blood vessels, catheters, blood bags,
In tools that come into direct contact with blood, such as artificial kidneys, the adhesion of blood components such as plasma proteins and platelets and the formation of thrombus resulting therefrom are inevitable problems. Particularly, in the case of a membrane used for a blood purifier, the adhesion of blood components directly leads to a decrease in the performance of the membrane, which is an important problem.
【０００３】従来、血液浄化器用の膜の素材としては、
セルロースアセテート、ポリオレフィン、ポリイミド、
ポリカーボネイト、ポリアリレート、ポリエステル、ポ
リアクリロニトリル・ポリメタクリル酸メチル・ポリア
ミド・ポリスルホン系樹脂等の高分子化合物が用いられ
てきた。これらの中でも、特にポリスルホン系樹脂は、
耐熱安定性、耐酸・耐アルカリ性に優れていることか
ら、近年広く使用されてきている。しかしその一方で、
その素材自身の疎水性のために、血液成分、特に血漿蛋
白や血小板の付着による性能の経時的な劣化は、避けら
れないものであった。かかる疎水性膜の欠点を解決する
ために該膜を親水化する手段として、製膜原液中に親水
性高分子を添加する方法（例えば特公平２−１８６９５
号公報、特開昭６１−９３８０１号公報、特開昭６１−
２３８３０６号公報、特開昭６３−９７２０５号号公報
など）があるが、一般にこの製膜原液中の親水性高分子
は膜の造孔剤としての役割も果たしており、製膜後洗浄
により取り除く必要があり、洗浄後の膜中には少量の親
水性高分子のみが残る。このような方法により製造され
た膜であっても、通常の使用に際しては血液成分の付着
をある程度抑制 することができるが、使用する患者の
血中成分の活性が高い場合などには必ずしも充分に血液
成分の付着を抑制 できるとは言えない。また、製膜後
材料表面に親水性高分子を固定化する方法（例えば特開
平６−２３８１３９号公報）があるが、この方法ではあ
る程度高い密度で親水性高分子を固定化しなければなら
ず、膜本来の透過性を低下させる危険がある。さらに、
血液成分と膜表面との相互作用の発現機序は非常に複雑
であり、膜の組成が微妙に変化するだけで、血液成分の
付着を抑制 するための最適な親水性高分子や処理条件
は異なる。現実に親水性高分子を導入することによりか
えって抗血小板付着性が低下する場合すらある。つま
り、現在までは高物質透過性、及び高い抗血小板付着性
の二つの性能を兼ね備えたポリスルホン系膜は実現され
ていない。Conventionally, as a material of a membrane for a blood purifier,
Cellulose acetate, polyolefin, polyimide,
High molecular compounds such as polycarbonate, polyarylate, polyester, polyacrylonitrile, polymethyl methacrylate, polyamide and polysulfone resin have been used. Among these, polysulfone-based resins, in particular,
It has been widely used in recent years because of its excellent heat resistance, acid resistance and alkali resistance. But on the other hand,
Due to the hydrophobicity of the material itself, deterioration over time due to the adhesion of blood components, particularly plasma proteins and platelets, has been inevitable. As a means for hydrophilizing the hydrophobic film in order to solve the drawbacks of the hydrophobic film, a method of adding a hydrophilic polymer to a film forming stock solution (for example, Japanese Patent Publication No. 2-18695)
JP, JP-A-61-93801, JP-A-61-93801
238306, JP-A-63-97205, etc.), but generally, the hydrophilic polymer in the film-forming stock solution also serves as a pore-forming agent for the film, and thus needs to be removed by washing after film-forming. And only a small amount of hydrophilic polymer remains in the membrane after washing. Even with a membrane manufactured by such a method, the adhesion of blood components can be suppressed to some extent during normal use, but it is not necessarily sufficient when the blood components of the patient to be used have high activity. It cannot be said that the adhesion of blood components can be suppressed. Further, there is a method of immobilizing a hydrophilic polymer on the material surface after film formation (for example, JP-A-6-238139). In this method, the hydrophilic polymer must be immobilized at a somewhat high density. There is a danger that the intrinsic permeability of the membrane will be reduced. further,
The mechanism of the interaction between the blood components and the membrane surface is very complicated, and the optimal hydrophilic polymer and processing conditions for suppressing the adhesion of the blood components are limited only by subtle changes in the membrane composition. different. In fact, the introduction of a hydrophilic polymer may even lower the antiplatelet adhesion. That is, to date, a polysulfone-based membrane having both the properties of high substance permeability and high antiplatelet adhesion has not been realized.
【０００４】[0004]
【発明が解決しようとする課題】本発明者は従来の技術
の改良を目指し、高い物質透過性をもち、なお且つ血漿
蛋白や血小板等の血液成分の付着も少ない分離膜、およ
びかかる分離膜を内蔵した抗血小板付着性を有する血液
浄化器を提供することを目的とする。DISCLOSURE OF THE INVENTION The present inventor aims to improve the prior art by providing a separation membrane having a high substance permeability and less adhesion of blood components such as plasma proteins and platelets, and such a separation membrane. An object of the present invention is to provide a built-in blood purifier having antiplatelet adhesion.
【０００５】[0005]
【課題を解決するための手段】上記目的を達成するため
に、本発明は次の構成を有する。すなわち、 １．「ポリビニルピロリドンを含むポリスルホン系樹脂
よりなる膜の表面の少なくとも一部にポリアルキレング
リコールが存在することを特徴とする分離膜。」 ２．「ポリアルキレングリコールが不溶化処理されてい
ることを特徴とする前記分離膜。」 ３．「ポリアルキレングリコールが0.01ng/cm2以上、50
0ng/cm2以下の割合で存在することを特徴とする前記い
ずれかの分離膜。」 ４．「ポリアルキレングリコールが0.05ng/cm2以上、30
0ng/cm2以下の割合で存在することを特徴とする前記い
ずれかの分離膜。」 ５．「血液浄化用である前記いずれかに記載の分離
膜。」 ６．「前記分離膜を内蔵する血液浄化器。」In order to achieve the above object, the present invention has the following arrangement. That is, 1. 1. A separation membrane characterized in that polyalkylene glycol is present on at least a part of the surface of a membrane made of a polysulfone-based resin containing polyvinylpyrrolidone. 2. "The separation membrane, wherein the polyalkylene glycol has been insolubilized." `` Polyalkylene glycol is 0.01 ng / cm2 or more, 50
Any of the above separation membranes, wherein the separation membrane is present at a rate of 0 ng / cm2 or less. 4. `` Polyalkylene glycol is 0.05 ng / cm2 or more, 30
Any of the above separation membranes, wherein the separation membrane is present at a rate of 0 ng / cm2 or less. "5. 5. The separation membrane according to any one of the above, which is for blood purification. "A blood purifier incorporating the separation membrane."
【０００６】[0006]
【発明の実施の形態】本発明の分離膜においては、ポリ
ビニルピロリドンを含有するポリスルホン系樹脂を主成
分として基体として使用する。ポリスルホン系樹脂は、
骨格にスルホン基をもつポリマーであればよく、さらに
式（1）の繰り返し単位からなるものが好ましいが、官
能基を含んでいたりアルキル系のものであってもよく、
また共重合していてもよい。BEST MODE FOR CARRYING OUT THE INVENTION In a separation membrane of the present invention, a polysulfone resin containing polyvinylpyrrolidone is used as a main component as a substrate. Polysulfone resin is
Any polymer having a sulfone group in the skeleton is preferable, and a polymer having a repeating unit of the formula (1) is preferable, but a polymer having a functional group or an alkyl group may be used.
Further, they may be copolymerized.
【化１】 Embedded image
【０００７】分離膜に含有されるポリビニルピロリドン
の分子量は特に限定されるものではないが、市販の1
万、4万、16万、36万のもの、もしくはこれらの混合物
を用いることができる。[0007] The molecular weight of polyvinylpyrrolidone contained in the separation membrane is not particularly limited.
Those of 10,000, 40,000, 160,000 and 360,000 or a mixture thereof can be used.
【０００８】また、本発明の分離膜におけるポリスルホ
ン樹脂とポリビニルピロリドンの構成比は、特に限定さ
れるものではないが、分離膜の機械的強度を保つ意味か
ら、ポリスルホン９９〜７０％、ポリビニルピロリドン
１〜３０％の範囲であることが好ましい。The composition ratio of the polysulfone resin and polyvinylpyrrolidone in the separation membrane of the present invention is not particularly limited, but from the viewpoint of maintaining the mechanical strength of the separation membrane, 99 to 70% of polysulfone and polyvinylpyrrolidone 1 are used. It is preferably in the range of 30% to 30%.
【０００９】本発明におけるポリビニルピロリドンを含
むポリスルホン系膜を製造するにあっては、例えば特公
平2-18695号公報、特開昭61-93801号公報、特開昭61-23
8306号公報等に開示されている製造方法を用いればよ
く、何等制限を加えるものではない。In producing the polysulfone-based membrane containing polyvinylpyrrolidone in the present invention, for example, Japanese Patent Publication No. 2-18695, Japanese Patent Application Laid-Open No. 61-93801, and Japanese Patent Application Laid-Open No. 61-23
The manufacturing method disclosed in Japanese Patent Publication No. 8306 or the like may be used without any limitation.
【００１０】本発明におけるポリアルキレングリコール
は例えばポリエチレングリコールやポリプロピレングリ
コールに代表される主鎖中に酸素原子を含む鎖状高分子
であるが、ポリアルキレングリコールがグラフトしたポ
リマーであっていてもよい。ポリアルキレングリコール
は、表面において0.01〜500ng/cm2、0.05〜300ng/cm2の
範囲の量であることが好ましい。The polyalkylene glycol in the present invention is a chain polymer containing an oxygen atom in the main chain typified by, for example, polyethylene glycol or polypropylene glycol, but may be a polymer grafted with polyalkylene glycol. The amount of the polyalkylene glycol on the surface is preferably in the range of 0.01 to 500 ng / cm2, 0.05 to 300 ng / cm2.
【００１１】そしてポリアルキレングリコールは不溶化
されていることが好ましい。The polyalkylene glycol is preferably insolubilized.
【００１２】ポリアルキレングリコールの不溶化を行う
にはポリビニルピロリドンを含むポリスルホン系の基体
膜をポリアルキレングリコール溶液（好ましくは水溶
液）に、浸漬などにより接触した状態で放射線を照射す
る方法が挙げられる。In order to insolubilize the polyalkylene glycol, a method of irradiating radiation with a polysulfone-based base film containing polyvinylpyrrolidone in contact with a polyalkylene glycol solution (preferably an aqueous solution) by immersion or the like can be used.
【００１３】本発明においては、かかる分離膜をプラス
ティックケースなどに内蔵することにより、血液浄化器
として好ましく用いることができる。本発明における血
液浄化器とは、血液透析器、血液濾過器、血液濾過透析
器、血漿分離器等の血液処理用の膜を含有するモジュー
ルである。また、ポリビニルピロリドンを含むポリスル
ホン系膜を含有する血液透析器、血液濾過器、血液濾過
透析器、血漿分離器等の血液浄化器を抗血小板付着性化
する場合であれば、該血液浄化器内の膜および少なくと
も血液が接触する部分全てにポリアルキレングリコール
水溶液が接触した状態で放射線処理すれば、膜表面ばか
りでなく、血液浄化器端部やヘッダーの内側などの血液
が接触する部位の全てを抗血小板付着性化することが可
能であり、例えば血液浄化器端部での血液凝固を軽減す
ることも可能である。In the present invention, by incorporating such a separation membrane in a plastic case or the like, it can be preferably used as a blood purifier. The blood purifier in the present invention is a module containing a blood processing membrane such as a hemodialyzer, a hemofilter, a hemofiltration dialyzer, and a plasma separator. Further, if a blood purifier such as a hemodialyzer, a hemofilter, a hemofiltration dialyzer, or a plasma separator containing a polysulfone-based membrane containing polyvinylpyrrolidone is made to have antiplatelet adhesion, the inside of the blood purifier may be used. If radiation treatment is performed with the polyalkylene glycol aqueous solution in contact with the membrane and at least all parts that come into contact with blood, not only the membrane surface, but also all the parts that come into contact with blood, such as the end of the blood purifier and the inside of the header. It can be made antiplatelet adherent, for example, to reduce blood coagulation at the end of the blood purifier.
【００１４】ポリアルキレングリコール水溶液のポリア
ルキレングリコールの分子量および水溶液の濃度は、特
に限定するものではないが、一般には低分子量、低濃度
の組み合わせであれば比較的抗血小板付着性化の程度は
低く、分子量が高くなるほど、また濃度が高くなるほど
抗血小板付着性化の程度は高くなる。しかし本発明の製
造方法ではポリアルキレングリコールの分子量を選択す
ることにより水溶液の濃度が1〜20000ppmと比較的低濃
度であっても十分な抗血小板付着性を得ることができる
ので抗血小板付着性化に対するコストを低く抑えること
ができ、このことは本発明の効果の一つである。他方、
高分子量、高濃度の組み合わせになると、膜表面にポリ
アルキレングリコール鎖が結合するだけでなくポリアル
キレングリコール鎖同士が互いに架橋してしまうため、
ポリアルキレングリコール鎖の運動性が損なわれ、思っ
たほど抗血小板付着性を付与できないばかりか、膜表面
でポリアルキレングリコールがゲル層を形成してしまう
ため、物質透過性能が低下する傾向もある。The molecular weight of the polyalkylene glycol and the concentration of the aqueous solution of the polyalkylene glycol in the aqueous solution of the polyalkylene glycol are not particularly limited. The higher the molecular weight and the higher the concentration, the higher the degree of antiplatelet adhesion. However, in the production method of the present invention, by selecting the molecular weight of the polyalkylene glycol, sufficient antiplatelet adhesion can be obtained even when the concentration of the aqueous solution is relatively low, such as 1 to 20,000 ppm. Cost can be kept low, which is one of the effects of the present invention. On the other hand,
When the combination of high molecular weight and high concentration, not only the polyalkylene glycol chains are bonded to the membrane surface but also the polyalkylene glycol chains are cross-linked to each other,
The mobility of the polyalkylene glycol chain is impaired, so that not only anti-platelet adhesion cannot be imparted as expected, but also because the polyalkylene glycol forms a gel layer on the membrane surface, there is also a tendency that the substance permeation performance is reduced.
【００１５】但しポリアルキレングリコール水溶液の条
件は、ポリスルホン系膜中のポリビニルピロリドンの含
有比率や、膜の形状や細孔径、ポリアルキレングリコー
ル水溶液に対する膜の量など、また希望する抗血小板付
着性の程度により、個々の場合について最適な条件は異
なる。The conditions of the aqueous polyalkylene glycol solution include, for example, the content ratio of polyvinylpyrrolidone in the polysulfone-based membrane, the shape and pore size of the membrane, the amount of the membrane with respect to the aqueous polyalkylene glycol solution, and the desired degree of antiplatelet adhesion. Optimum conditions are different for each case.
【００１６】放射線の照射量は特に限定されるものでは
なく、抗血小板付着性化したい膜表面や血液浄化器の血
液が接触する面にポリアルキレングリコール鎖が結合す
るだけの照射量があればよく、15〜35kGy程度の吸収エ
ネルギーでの照射が好適に用いられる。また、抗血小板
付着性を付与すると同時に滅菌を行うこともできる。こ
の場合、放射線の照射量は一般に滅菌線量以上であれば
幾らでも良いが、膜の強度劣化の問題や経済性を考慮し
て、25〜35kGy程度が望ましい。但し、放射線に対する
膜の劣化が無視しうる範囲である場合や経済性を考慮す
る必要のない場合には、放射線の照射量がこの範囲であ
る必要はない。The irradiation dose of radiation is not particularly limited, and it is sufficient that the irradiation dose is such that the polyalkylene glycol chains are bonded to the surface of the membrane to be made antiplatelet-adherent or the blood contact surface of the blood purifier. Irradiation with an absorption energy of about 15 to 35 kGy is preferably used. In addition, sterilization can be performed simultaneously with imparting antiplatelet adhesion. In this case, the irradiation dose of radiation is generally not limited as long as it is equal to or higher than the sterilization dose, but is preferably about 25 to 35 kGy in consideration of the problem of membrane strength deterioration and economy. However, when the deterioration of the film due to the radiation is within a negligible range or when it is not necessary to consider economics, the radiation dose does not need to be within this range.
【００１７】ポリスルホン系膜の表面でポリアルキレン
グリコールを不溶化するために放射線を使用する方法
は、ポリアルキレングリコール鎖を導入するための特別
の反応性基を必要としないため好ましい。一般にはポリ
スルホン系樹脂を含有する素材に反応性基を導入するこ
とは素材の価格が上昇するだけでなく、製造方法にまで
制限が生まれる。例えばポリスルホン系中空糸膜を紡糸
する際、その素材であるポリスルホン系樹脂に反応性基
を導入すると、一般にその化学的性質が変わるので、原
液調製の際の溶解性や製膜性が大きく変わり、製造条件
全てを検討し直す必要がある。つまり、中空糸紡糸原液
の調整方法から、製糸条件、後処理条件、ケース組み込
み工程の条件まで全ての工程において検討の必要があ
り、その労力は膨大なものとなる。更には、反応性基の
導入により一般には素材分子間の結合力が弱まり、中空
糸の強伸度特性が低下するために、製糸安定性が悪くな
り、生産性の低下が懸念される。これに対して、上記に
記載の製造方法によれば、従来の膜の製造方法を何等手
直しする必要はなく、従来の製造プロセスにポリアルキ
レングリコール水溶液充填と放射線照射のプロセスを付
け加えるだけで良く、膜表面のみの反応であるため中空
糸膜の強伸度特性の悪化の心配もほとんどいらない。更
に、既に滅菌方法として放射線照射を採用している場合
は、製品滅菌時にポリアルキレングリコール水溶液をモ
ジュールケース内に充填するだけでよい。The method of using radiation to insolubilize the polyalkylene glycol on the surface of the polysulfone-based membrane is preferable because it does not require a special reactive group for introducing a polyalkylene glycol chain. In general, introducing a reactive group into a material containing a polysulfone-based resin not only increases the price of the material, but also limits the manufacturing method. For example, when spinning a polysulfone-based hollow fiber membrane, when a reactive group is introduced into the polysulfone-based resin that is the material, the chemical properties generally change, so that the solubility and film-forming properties during preparation of the stock solution greatly change, It is necessary to reconsider all manufacturing conditions. In other words, it is necessary to study all the processes from the method of preparing the hollow fiber spinning stock solution to the conditions of the spinning conditions, the post-treatment conditions, and the conditions of the case assembling process, and the labor becomes enormous. Further, the introduction of the reactive group generally weakens the bonding force between the material molecules and lowers the strength and elongation characteristics of the hollow fiber, so that the yarn production stability is deteriorated and there is a concern that the productivity may be reduced. On the other hand, according to the manufacturing method described above, there is no need to modify the conventional manufacturing method of the membrane at all, it is sufficient to add the process of filling the polyalkylene glycol aqueous solution and irradiating the conventional manufacturing process, Since the reaction is performed only on the membrane surface, there is almost no need to worry about the deterioration of the strength and elongation characteristics of the hollow fiber membrane. Further, when radiation irradiation has already been adopted as a sterilization method, it is only necessary to fill the module case with a polyalkylene glycol aqueous solution at the time of product sterilization.
【００１８】本発明における血液浄化器とは、血液透析
器、血液濾過器、血液濾過透析器、血漿分離器等の血液
処理用の分離膜を含有するモジュールである。The blood purifier in the present invention is a module containing a blood treatment separation membrane such as a hemodialyzer, a hemofilter, a hemofiltration dialyzer, a plasma separator and the like.
【００１９】[0019]
【実施例】以下に本発明を実施例に基づいて説明する。DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below based on embodiments.
【００２０】以下、用いた測定法は以下の通りである。Hereinafter, the measuring method used is as follows.
【００２１】（１）ポリエチレングリコール（以下PEG
と略す）の表面濃度の測定 後の各実施例、比較例で説明するγ線照射後蒸留水にて
洗浄したミニモジュール（もしくは小型モジュール）を
解体し中空糸を取り出した。取り出した中空糸を５０
℃、０.５torr にて１０時間乾燥した。乾燥した中空糸
１０〜１００mgを試験管に取り、無水酢酸とパラトルエ
ンスルホン酸の混合溶液２mlを添加し、１２０℃で約１
時間アセチル化し、冷却後２mlの純水で器壁を洗い落と
した後、２０％炭酸ナトリウム溶液で中和し、トリクロ
ロメタン５mlで抽出し、ガスクロマトグラフィー法（以
下GCと言う）で分析した。(1) Polyethylene glycol (hereinafter PEG)
The mini-module (or small module) washed with distilled water after γ-irradiation described in each of Examples and Comparative Examples after measurement of the surface concentration was disassembled and the hollow fiber was taken out. 50 hollow fibers taken out
It was dried at 0.5 torr for 10 hours. 10 to 100 mg of the dried hollow fiber is placed in a test tube, and 2 ml of a mixed solution of acetic anhydride and paratoluenesulfonic acid is added thereto.
After acetylation for 2 hours, the vessel wall was washed with 2 ml of pure water after cooling, neutralized with a 20% sodium carbonate solution, extracted with 5 ml of trichloromethane, and analyzed by gas chromatography (hereinafter referred to as GC).
【００２２】膜表面上に存在しているPEG量は、予め作
成した検量線から求めた。The amount of PEG present on the membrane surface was determined from a previously prepared calibration curve.
【００２３】PEGの表面濃度はGCにより求めたPEG量を、
窒素吸着法により求めた膜の細孔内部を含む表面積で割
り、求めた。The surface concentration of PEG is determined by the amount of PEG determined by GC,
It was determined by dividing by the surface area including the inside of the pores of the membrane determined by the nitrogen adsorption method.
【００２４】（２）in vitro 血小板付着実験 洗浄後のミニモジュールの血液入口から中空糸中空部分
に、３．８％クエン酸ナトリウム水溶液を１０容量％添
加した家兎新鮮血１０ccを０.５７ml/minで流し、その
後生理食塩水にて洗浄した後、グルタルアルデヒド固定
し、中空糸分離膜をミニモジュールから切り出して凍結
乾燥した。この中空糸の内表面を（フィールドエミッシ
ョン型走査電子顕微鏡）FE-SEMにて観察し、０.０１cm2
の面積中の付着血小板数を数えた。(2) In vitro Platelet Adhesion Experiment 10 cc of rabbit fresh blood containing 10% by volume of a 3.8% aqueous sodium citrate solution was added to the hollow fiber hollow portion from the blood inlet of the washed mini-module after washing by 0.57 ml / volume. After washing with physiological saline, glutaraldehyde was fixed, and the hollow fiber separation membrane was cut out from the mini-module and freeze-dried. The inner surface of the hollow fiber was observed with a FE-SEM (field emission scanning electron microscope) to obtain a 0.01 cm 2
The number of adhered platelets in the area of was counted.
【００２５】（３）in vivo 血小板付着実験 体重約３kgの家兎の頚動脈から導き出した血液を、洗浄
後の小型モジュールの血液入口から中空糸中空部に通
し、小型モジュールの血液出口から該家兎の頚静脈へ戻
す体外循環試験を行った。血液の流速は５０ml／min、
抗凝固剤としてヘパリンを１８IU 初期投与し、更に６
０IU／hr 持続投与しながら３時間循環した。体外循環
終了後、in vitro 血小板付着実験と同様に生理食塩水
にて洗浄後グルタルアルデヒド固定し、モジュールから
切り出した中空糸及びモジュールヘッダーを凍結乾燥し
た。この中空糸の内表面及びモジュールヘッダー内側
（血液接触面）をFE-SEMにて観察し、０.０１cm2の面積
中の付着血小板数を数えた。(3) In Vivo Platelet Adhesion Experiment Blood derived from the carotid artery of a rabbit weighing about 3 kg is passed through the hollow fiber hollow portion through the blood inlet of the small module after washing, and the rabbit is passed through the blood outlet of the small module. An extracorporeal circulation test was conducted to return to the jugular vein. The blood flow rate is 50 ml / min,
18 IU of heparin was initially administered as an anticoagulant, and
Circulation was performed for 3 hours while continuously administering 0 IU / hr. After the end of extracorporeal circulation, the cells were washed with physiological saline and fixed with glutaraldehyde in the same manner as in the in vitro platelet adhesion experiment, and the hollow fiber cut out from the module and the module header were freeze-dried. The inner surface of the hollow fiber and the inside of the module header (blood contact surface) were observed by FE-SEM, and the number of adhered platelets in an area of 0.01 cm 2 was counted.
【００２６】（４）in vitro β２-ミクログロブリン
（以下β２-MG）除去性能の測定 フィルター処理を行った牛血清 ３０ml に、ヒトβ２-M
Gを５mg/mlの濃度で溶解し、洗浄後のミニモジュールの
血液入口からの中空糸中空部分に１ml/minで灌流し、中
空糸外側には３７℃に保ったPBS１４０mlを２０ml/min
の速度で密閉形で灌流した。４時間灌流後中空糸内側・
外側灌流液を採取し、クリアランスを算出した。クリア
ランスは式（２）により算出した。(4) Measurement of in vitro β2-microglobulin (hereinafter β2-MG) removal performance Human β2-M was added to 30 ml of the filtered bovine serum.
G was dissolved at a concentration of 5 mg / ml, and the hollow fiber was perfused at 1 ml / min from the blood inlet of the mini-module after washing, and 140 ml of PBS maintained at 37 ° C. was added to the outside of the hollow fiber at 20 ml / min.
Perfusion in closed form at a speed of. After perfusion for 4 hours
The outer perfusate was collected and the clearance was calculated. The clearance was calculated by equation (2).
【数１】 ここでCL：クリアランス(ml/min)、CBi：モジュール入
口側濃度(mg/ml)、 CBo：モジュール出口側濃度(mg/m
l)、QB：モジュール供給液量(ml/min)である。(Equation 1) Where CL: clearance (ml / min), CBi: concentration at the module inlet (mg / ml), CBo: concentration at the module outlet (mg / m)
l), QB: Module supply liquid volume (ml / min).
【００２７】また、実施例、比較例に使用した試料中空
糸は次のようにして準備した。The sample hollow fibers used in the examples and comparative examples were prepared as follows.
【００２８】実施例１〜１１、比較例１〜3 ポリスルホン（ユ―デルP―３５００）１８部、ポリビ
ニルピロリドン（K３０）２部をN,N-ジメチルアセトア
ミド（以下DMAcと言う）８０部に加え、加熱溶解した。
この製膜原液をオリフィス型二重円筒型口金より吐出し
空気中を２００mm通過した後、水１００％の凝固浴中に
導き中空糸を得た。この際、内部注入液にはDMAc５０
部、水５０部の注入液を用いた。該中空糸の内径は０.
２mm、膜厚は０.０４mmであった。Examples 1 to 11 and Comparative Examples 1 to 3 18 parts of polysulfone (Udel P-3500) and 2 parts of polyvinylpyrrolidone (K30) were added to 80 parts of N, N-dimethylacetamide (hereinafter referred to as DMAc). And dissolved by heating.
This membrane-forming stock solution was discharged from an orifice-type double cylindrical die, passed through the air 200 mm, and then guided into a coagulation bath of 100% water to obtain a hollow fiber. At this time, DMAc50
And 50 parts of water. The inner diameter of the hollow fiber is 0.5.
The thickness was 2 mm and the film thickness was 0.04 mm.
【００２９】このようにして準備したポリスルホン中空
糸分離膜を４０本束ね、中空糸中空部を閉塞しないよう
にエポキシ系ポッティング剤で両末端をガラス管モジュ
ールケースに固定し、図１に示すミニモジュールを作成
した。該ミニモジュールの直径は約７mm、長さは約１０
cmである。The polysulfone hollow fiber separation membranes thus prepared were bundled in a bundle of 40, and both ends were fixed to a glass tube module case with an epoxy potting agent so as not to block the hollow portion of the hollow fiber. It was created. The diameter of the mini module is about 7mm and the length is about 10
cm.
【００３０】該ミニモジュールの血液流入口と透析液流
出口をシリコンチューブで繋ぎ、血液流出口から種種の
ポリエチングリコール水溶液またはポリビニルピロリド
ン水溶液１００mlを１００ml/minの流速で流し、ミニモ
ジュール内に空気が入らないようにキャップをし、３０
kGyでγ線を照射した。ミニモジュールに充填したポリ
エチレングリコール水溶液およびポリビニルピロリドン
水溶液の溶質の数平均分子量および水溶液濃度を表１に
示す。γ線照射後のミニモジュールの血液流入口と透析
液流出口をシリコンチューブで繋ぎ、血液流出口から蒸
留水５００mlを１００ml/minの流速で流し中空糸および
モジュール内部を洗浄し、in vitro 血小板付着実験お
よびin vitro β２-MG除去性能の測定を行った。各ミニ
モジュールの測定結果を蒸留水を充填しγ線照射した比
較例１の結果を１００とした相対値で表１に示す。The blood inlet and the dialysate outlet of the mini-module are connected by a silicon tube, and 100 ml of various polyethyne glycol aqueous solutions or polyvinylpyrrolidone aqueous solutions are flowed from the blood outlet at a flow rate of 100 ml / min. Cap to prevent
Irradiated with γ-rays at kGy. Table 1 shows the number average molecular weight and the aqueous solution concentration of the solutes of the aqueous polyethylene glycol solution and the aqueous solution of polyvinyl pyrrolidone filled in the mini-module. The blood inlet and dialysate outlet of the mini-module after γ-ray irradiation are connected by a silicon tube, and 500 ml of distilled water is flowed from the blood outlet at a flow rate of 100 ml / min to wash the hollow fiber and the inside of the module, and to adhere platelets in vitro Experimental and in vitro β2-MG removal performance measurements were performed. The measurement results of each mini-module are shown in Table 1 as relative values when the results of Comparative Example 1 in which distilled water was filled and γ-ray irradiation was performed were set to 100.
【００３１】実施例１２、比較例４ 実施例１と同様に紡糸したポリスルホン中空糸分離膜
３,５００本を束ね、中空糸中空部を閉塞しないように
ウレタン系ポッティング剤で中空糸分離膜の両末端をポ
リスチレン製モジュールケースに固定し、モジュールケ
ース両端部にポリスチレン製モジュールヘッダーを装着
し、図２に示す小型モジュールを作成した。該小型モジ
ュールの胴体部直径は約３cm、長さは約１５cmである。
この小型モジュールの血液流入口と透析液流出口をシリ
コンチューブで繋ぎ、血液流出口から蒸留水もしくは分
子量６０００、濃度２０００ppmのポリエチングリコー
ル水溶液５００mlを１００ml/minの流速で流し、小型モ
ジュール内に空気が入らないようにキャップをし、３０
kGyのγ線を照射した。γ線照射後の小型モジュールの
血液流入口と透析液流出口をシリコンチューブで繋ぎ、
血液流出口から蒸留水１０００mlを１００ml/minの流速
で流し中空糸およびモジュール内部を洗浄した後、in v
ivo 血小板付着実験を行った。また同様に処理した小型
モジュールを解体し、取り出した中空糸を用いて実施例
１と同様にミニモジュールを作成し、invitro β２-MG
除去性能の測定を行った。さらに解体して取り出した中
空糸を用いてポリエチレングリコールの膜表面結合密度
を測定した。実施例１２の測定結果を蒸留水を充填しγ
線照射した比較例４の結果を１００とした相対値で表６
に示す。Example 12 and Comparative Example 4 3,500 polysulfone hollow fiber separation membranes spun in the same manner as in Example 1 were bundled, and both of the hollow fiber separation membranes were coated with a urethane-based potting agent so as not to block the hollow part of the hollow fiber. The ends were fixed to a polystyrene module case, and polystyrene module headers were attached to both ends of the module case, thereby producing a small module shown in FIG. The small module has a body diameter of about 3 cm and a length of about 15 cm.
The blood inlet and dialysate outlet of this small module are connected by a silicon tube, and distilled water or 500 ml of an aqueous solution of polyethene glycol having a molecular weight of 6000 and a concentration of 2000 ppm flows at a flow rate of 100 ml / min from the blood outlet, and air flows into the small module. Cap to prevent
Irradiated with kGy gamma rays. Connect the blood inlet and dialysate outlet of the small module after gamma irradiation with a silicon tube,
After flowing 1000 ml of distilled water at a flow rate of 100 ml / min from the blood outlet to wash the hollow fiber and the inside of the module, inv
An ivo platelet adhesion experiment was performed. In addition, the small module treated in the same manner was disassembled, and a mini-module was prepared in the same manner as in Example 1 using the taken out hollow fiber, and in vitro β2-MG
The removal performance was measured. Further, using the hollow fiber taken out from the disassembly, the membrane surface binding density of polyethylene glycol was measured. The measurement result of Example 12 was filled with distilled water and γ
Table 6 shows relative values with the result of Comparative Example 4 irradiated with X-rays taken as 100.
Shown in
【００３２】[0032]
【表１】 [Table 1]
【００３３】[0033]
【表２】 [Table 2]
【００３４】実施例１〜11の結果が示すとおり、ポリエ
チレングリコールを膜表面に結合することにより付着血
小板数は減少し、抗血小板付着性が向上することがわか
る。更に実施例１２の結果から判るように、ヘッダー内
面の付着血小板数も減少することから血液浄化器の血液
接触面全体での抗血小板付着性化が可能であることも分
かる。また、β２-MG除去能は膜表面にポリエチレング
リコールを不溶化していない分離膜の性能をほぼ維持し
ており、物質透過性能の低下がほとんどないことが分か
る。As shown in the results of Examples 1 to 11, it can be seen that the number of adhered platelets is reduced by binding polyethylene glycol to the membrane surface, and the antiplatelet adhesion is improved. Furthermore, as can be seen from the results of Example 12, since the number of platelets adhered to the inner surface of the header is also reduced, it can be seen that antiplatelet adhesion can be achieved on the entire blood contact surface of the blood purifier. Further, it can be seen that the β2-MG removal ability almost maintains the performance of the separation membrane in which polyethylene glycol is not insolubilized on the membrane surface, and there is almost no decrease in the substance permeation performance.
【００３５】比較例２、３では、親水性高分子として一
般に知られているポリビニルピロリドンを膜表面に不溶
化しても、ポリビニルピロリドンを含むポリスルホン膜
に対しては抗血小板付着性化の効果がないばかりか、か
えって血小板が付着しやすくなっている。このことから
ポリビニルピロリドンを含むポリスルホン膜を抗血小板
付着性化するためには親水性高分子であればどのような
ものでもよいと言うわけではなく、ポリアルキレングリ
コールを膜表面に付着させることが重要であることがわ
かる。In Comparative Examples 2 and 3, even if polyvinylpyrrolidone, which is generally known as a hydrophilic polymer, was insolubilized on the membrane surface, the polysulfone membrane containing polyvinylpyrrolidone had no effect on antiplatelet adhesion. Not only that, platelets are more likely to adhere. For this reason, it is not necessarily the case that any hydrophilic polymer can be used to make a polysulfone membrane containing polyvinylpyrrolidone antiplatelet-adhesive. It is important to attach a polyalkylene glycol to the membrane surface. It can be seen that it is.
【００３６】実施例１３ 実施例１２と同様に処理したγ線照射後の小型モジュー
ルを解体して中空糸を取り出し、その中空糸を５０℃、
０.５torr にて１０時間乾燥した。乾燥した中空糸20g
を200mlのDMAcに投入し、室温にて２時間撹拌した後、D
MAc不溶解分を濾別した。このDMAc不溶解分を新しいDMA
c200mlに再び投入し、室温にて2時間撹拌した。この操
作を３回繰り返し得られたDMAc不溶解分を蒸留水にて洗
浄し、５０℃、０.５torr にて１０時間乾燥した。乾燥
した不溶解分をKBr法にてIR測定した。また同時に、こ
の不溶解分に１０〜１００mgを試験管に取り、無水酢酸
とパラトルエンスルホン酸の混合溶液２mlを添加し、１
２０℃で約１時間アセチル化し、冷却後２mlの純水で器
壁を洗い落とした後、２０％炭酸ナトリウム溶液で中和
し、トリクロロメタン５mlで抽出し、GCで分析した。Example 13 A small module after irradiation with γ-rays treated in the same manner as in Example 12 was disassembled and a hollow fiber was taken out.
It was dried at 0.5 torr for 10 hours. 20g of dried hollow fiber
Was added to 200 ml of DMAc and stirred at room temperature for 2 hours.
MAc insolubles were filtered off. This DMAc insoluble matter is transferred to a new DMA
c 200 ml was added again, and the mixture was stirred at room temperature for 2 hours. This operation was repeated three times, and the resulting DMAc-insoluble portion was washed with distilled water and dried at 50 ° C. and 0.5 torr for 10 hours. The dried insoluble matter was subjected to IR measurement by the KBr method. At the same time, 10 to 100 mg of the insoluble matter was placed in a test tube, and 2 ml of a mixed solution of acetic anhydride and paratoluenesulfonic acid was added.
After acetylation at 20 ° C. for about 1 hour, after cooling, the vessel wall was washed off with 2 ml of pure water, neutralized with a 20% sodium carbonate solution, extracted with 5 ml of trichloromethane, and analyzed by GC.
【００３７】IR測定の結果、測定チャートには、ポリス
ルホンのベンゼン環に由来する1585cm-1、スルホニル基
に由来する1150cm-1の吸収、ポリビニルピロリドンの第
３アミド基に由来する1690cm-1の吸収が認められた。GC
の結果からは、ポリエチレングリコール由来のピークが
認められた。以上の結果から、ポリビニルピロリドンを
含むポリスルホン膜をポリエチレングリコール水溶液中
でガンマ線照射することにより、ポリスルホン、ポリビ
ニルピロリドン、ポリエチレングリコールの３成分が互
いに架橋することがわかった。As a result of IR measurement, the measurement chart shows that the absorption at 1585 cm-1 derived from the benzene ring of polysulfone, the absorption at 1150 cm-1 derived from the sulfonyl group, and the absorption at 1690 cm-1 derived from the tertiary amide group of polyvinylpyrrolidone were obtained. Was observed. GC
As a result, a peak derived from polyethylene glycol was observed. From the above results, it was found that the polysulfone, polyvinylpyrrolidone, and polyethylene glycol were mutually cross-linked by irradiating the polysulfone membrane containing polyvinylpyrrolidone with gamma rays in an aqueous polyethylene glycol solution.
【００３８】[0038]
【発明の効果】以上述べた如く、本発明による分離膜は
高い抗血小板付着性をもち、尚且つ高い物質透過性能を
もった分離膜であり、血液浄化用に有効である。As described above, the separation membrane according to the present invention is a separation membrane having high antiplatelet adhesion and high substance permeation performance, and is effective for blood purification.
【図１】本発明実施例１〜１１、比較例１〜３に用いた
ミニモジュールの模式図である。FIG. 1 is a schematic diagram of a mini-module used in Examples 1 to 11 of the present invention and Comparative Examples 1 to 3.
【図２】本発明実施例１２、比較例４に用いた小型モジ
ュールの模式図である。FIG. 2 is a schematic view of a small module used in Example 12 of the present invention and Comparative Example 4.
１. 血液入口 ２. ポッティング部 ３. 透析液入口 ４. 中空糸分離膜 ５. ガラス管モジュールケース ６. 透析液入口 ７. 血液出口 ８. モジュールヘッダー ９. モジュールケース 1. Blood inlet 2. Potting section 3. Dialysate inlet 4. Hollow fiber separation membrane 5. Glass tube module case 6. Dialysate inlet 7. Blood outlet 8. Module header 9. Module case
Claims (6)
系樹脂よりなる膜の表面の少なくとも一部にポリアルキ
レングリコールが存在することを特徴とする分離膜。1. A separation membrane characterized in that a polyalkylene glycol is present on at least a part of the surface of a membrane made of a polysulfone resin containing polyvinylpyrrolidone.
されていることを特徴とする請求項１記載の分離膜。2. The separation membrane according to claim 1, wherein said polyalkylene glycol has been insolubilized.
以上、500ng/cm2以下の割合で存在することを特徴とす
る請求項１または請求項２記載の分離膜。3. The method according to claim 1, wherein said polyalkylene glycol is 0.01 ng / cm @ 2.
The separation membrane according to claim 1 or 2, wherein the separation membrane is present at a rate of 500 ng / cm2 or less.
以上、300ng/cm2以下の割合で存在することを特徴とす
る請求項１または請求項２記載の分離膜。4. The method according to claim 1, wherein said polyalkylene glycol is 0.05 ng / cm 2.
The separation membrane according to claim 1 or 2, wherein the separation membrane is present at a rate of 300 ng / cm2 or less.
記載の分離膜。5. The separation membrane according to claim 1, which is for blood purification.
器。6. A blood purifier incorporating the separation membrane according to claim 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21051897A JP3498543B2 (en) | 1997-08-05 | 1997-08-05 | Separation membrane and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21051897A JP3498543B2 (en) | 1997-08-05 | 1997-08-05 | Separation membrane and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1147570A true JPH1147570A (en) | 1999-02-23 |
| JP3498543B2 JP3498543B2 (en) | 2004-02-16 |
Family
ID=16590706
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21051897A Expired - Fee Related JP3498543B2 (en) | 1997-08-05 | 1997-08-05 | Separation membrane and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3498543B2 (en) |
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| WO2004018085A1 (en) * | 2002-08-21 | 2004-03-04 | Toray Industries, Inc. | Modified substrate and process for producing modified substrate |
| JP2004275331A (en) * | 2003-03-14 | 2004-10-07 | Toray Ind Inc | Medical material and manufacturing method therefor |
| JP2005065711A (en) * | 2003-08-21 | 2005-03-17 | Toray Ind Inc | Absorption material and manufacturing method of the same |
| JP2005334318A (en) * | 2004-05-27 | 2005-12-08 | Toyobo Co Ltd | High strength and high water permeability hollow fiber membrane type hemocatharsis apparatus |
| JP2006288942A (en) * | 2005-04-14 | 2006-10-26 | Toyobo Co Ltd | Method for coating hollow-fiber hemocatharsis membrane with surface modifier, surface modifier coated hollow-fiber hemocatharsis membrane and surface modifier coated hollow-fiber hemocatharsis appliance |
| JP2011183384A (en) * | 2011-04-01 | 2011-09-22 | Toray Ind Inc | Adsorption material and manufacturing method for the same |
| EP2990099A1 (en) * | 2014-08-18 | 2016-03-02 | Fenwal, Inc. | Anti-thrombogenic porous membranes and methods for manufacturing such membranes |
-
1997
- 1997-08-05 JP JP21051897A patent/JP3498543B2/en not_active Expired - Fee Related
Cited By (10)
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|---|---|---|---|---|
| WO2004018085A1 (en) * | 2002-08-21 | 2004-03-04 | Toray Industries, Inc. | Modified substrate and process for producing modified substrate |
| JPWO2004018085A1 (en) * | 2002-08-21 | 2005-12-08 | 東レ株式会社 | Modified substrate and method for producing modified substrate |
| JP4810827B2 (en) * | 2002-08-21 | 2011-11-09 | 東レ株式会社 | Modified substrate and method for producing modified substrate |
| EP2543428A1 (en) * | 2002-08-21 | 2013-01-09 | Toray Industries, Inc. | Modified membrane substrate with reduced platelet adsorption and process for producing modified substrate |
| JP2004275331A (en) * | 2003-03-14 | 2004-10-07 | Toray Ind Inc | Medical material and manufacturing method therefor |
| JP2005065711A (en) * | 2003-08-21 | 2005-03-17 | Toray Ind Inc | Absorption material and manufacturing method of the same |
| JP2005334318A (en) * | 2004-05-27 | 2005-12-08 | Toyobo Co Ltd | High strength and high water permeability hollow fiber membrane type hemocatharsis apparatus |
| JP2006288942A (en) * | 2005-04-14 | 2006-10-26 | Toyobo Co Ltd | Method for coating hollow-fiber hemocatharsis membrane with surface modifier, surface modifier coated hollow-fiber hemocatharsis membrane and surface modifier coated hollow-fiber hemocatharsis appliance |
| JP2011183384A (en) * | 2011-04-01 | 2011-09-22 | Toray Ind Inc | Adsorption material and manufacturing method for the same |
| EP2990099A1 (en) * | 2014-08-18 | 2016-03-02 | Fenwal, Inc. | Anti-thrombogenic porous membranes and methods for manufacturing such membranes |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3498543B2 (en) | 2004-02-16 |
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